Photodynamic Therapy as an Adjuvant Therapy for Local-Partial Remission of Nasopharyngeal Carcinoma After Standard Therapy in Sardjito Hospital YOGYAKARTA a Five-Year-Overall Survival Rate Analysis Study

Background: The foremost problems of nasopharyngeal carcinoma (NPC) management are high loco-regional remission, local recurrence and spreading rate post therapy. Photodynamic therapy (PDT) has been done for treatment of tumors less than 1 cm in size and depth in a very difficult location, where radical excision by surgery was not possible. The aim of this study is determining 5-year-overall survival rate of local-partial remission of NPC after standard therapy followed by additional PDT.Method: The survival study is subjected to the 5 years-overall survival rate of local-partial remission. Photosensitizer (FoscanR) 0,15mg/kgBW was injected to NPC patients and followed by 20 joule/cm2, 642 wave length and 100 watts/cm2 irradiants non thermal laser illumination 96 hours after injection. The PDT result was confirmed with biopsy, CT scan, upper abdominal USG, thoracic radiograph and bone survey for 12 weeks after treatment. Follow up was done every 3 months in first year, continued every 6 months in the second year, and followed once a year. The sample collected from January 2005 to December 2010, and 33 cases met the inclusion and exclusion criterias, but only 20 cases were eligible inclusion criteria. The 5 years-overall survival was defined as the time from diagnosis to death from any cause or last follow up, calculated by Kaplan Meier survival analysis.Results: The 5-year-overall survival rate was 50%.Conclusion: PDT as an additional treatment for small local-partial remission in NPC post treatment is an alternative therapy to improve the treatment outcome and survival rate

A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets

Objective: Gastric cancer is a major gastrointestinal malignancy for which targeted therapies are emerging as treatment options. This study sought to identify the most prevalent molecular targets in gastric cancer and to elucidate systematic patterns of exclusivity and co-occurrence among these targets, through comprehensive genomic analysis of a large panel of gastric cancers. Design: Using high-resolution single nucleotide polymorphism arrays, copy number alterations were profiled in a panel of 233 gastric cancers (193 primary tumours, 40 cell lines) and 98 primary matched gastric non-malignant samples. For selected alterations, their impact on gene expression and clinical outcome were evaluated. Results: 22 recurrent focal alterations (13 amplifications and nine deletions) were identified. These included both known targets (FGFR2, ERBB2) and also novel genes in gastric cancer (KLF5, GATA6). Receptor tyrosine kinase (RTK)/RAS alterations were found to be frequent in gastric cancer. This study also demonstrates, for the first time, that these alterations occur in a mutually exclusive fashion, with KRAS gene amplifications highlighting a clinically relevant but previously underappreciated gastric cancer subgroup. FGFR2-amplified gastric cancers were also shown to be sensitive to dovitinib, an orally bioavailable FGFR/VEGFR targeting agent, potentially representing a subtype-specific therapy for FGFR2-amplified gastric cancers. Conclusion: The study demonstrates the existence of five distinct gastric cancer patient subgroups, defined by the signature genomic alterations FGFR2 (9% of tumours), KRAS (9%), EGFR (8%), ERBB2 (7%) and MET (4%). Collectively, these subgroups suggest that at least 37% of gastric cancer patients may be potentially treatable by RTK/RAS directed therapies

Monitoring amyloid-β 42 conformational change using a spray-printed graphene electrode

Up to now, the reproducibility and stability of graphene-based electrochemical sensors have represented an obstacle to the development of practical biosensing techniques. In this paper we report a cost-effective and highly reproducible graphene-based electrochemical sensing platform to monitor the kinetic conformational change of amyloidogenic proteins. The sensor surface is spray-printed with a graphene oxide layer and then electrochemically reduced to achieve excellent sensitivity to the redox current. The reproducibility of these sensors in terms of redox peak position, intensity and electroactive area has been proved to be high. These sensors are used to monitor the conformational changes of amyloid-β 42 via the change in the oxidation current of tyrosine, which is caused by different electrochemical accessibility during the aggregation process. The aggregation process detected at these graphene electrochemical sensors shows a good correlation with the fluorescence assay. The proposed platform provides a complementary technique to aid understanding of the detailed process of amyloidogenic protein aggregation and the mechanism of neurodegenerative diseases as well as helping to promote the development of disease-prevention strategies

Nanostring-based multigene assay to predict recurrence for gastric cancer patients after surgery

10.1371/journal.pone.0090133PLoS ONE93-POLN

Risk assessment for the spread of Serratia marcescens within dental-unit waterline systems using Vermamoeba vermiformis

Vermamoeba vermiformis is associated with the biofilm ecology of dental-unit waterlines (DUWLs). This study investigated whether V. vermiformis is able to act as a vector for potentially pathogenic bacteria and so aid their dispersal within DUWL systems. Clinical dental water was initially examined for Legionella species by inoculating it onto Legionella selective-medium plates. The molecular identity/profile of the glassy colonies obtained indicated none of these isolates were Legionella species. During this work bacterial colonies were identified as a non-pigmented Serratia marcescens. As the water was from a clinical DUWL which had been treated with Alpron™ this prompted the question as to whether S. marcescens had developed resistance to the biocide. Exposure to Alpron™ indicated that this dental biocide was effective, under laboratory conditions, against S. marcescens at up to 1x108 colony forming units/millilitre (cfu/ml). V. vermiformis was cultured for eight weeks on cells of S. marcescens and Escherichia coli. Subsequent electron microscopy showed that V. vermiformis grew equally well on S. marcescens and E. coli (p = 0.0001). Failure to detect the presence of S. marcescens within the encysted amoebae suggests that V. vermiformis is unlikely to act as a vector supporting the growth of this newly isolated, nosocomial bacterium

Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas

Background: Cytotoxic chemotherapy remains the main systemic therapy for gastro-oesophageal adenocarcinoma, but resistance to chemotherapy is common, resulting in ineffective and often toxic treatment for patients. Predictive biomarkers for chemotherapy response would increase the probability of successful therapy, but none are currently recommended for clinical use. We used global gene expression profiling of tumour biopsies to identify novel predictive biomarkers for cytotoxic chemotherapy. Methods: Tumour biopsies from patients (n=14) with TNM stage IB–IV gastro-oesophageal adenocarcinomas receiving platinum-based combination chemotherapy were used as a discovery cohort and profiled with Affymetrix ST1.0 Exon Genechips. An independent cohort of patients (n=154) treated with surgery with or without neoadjuvant platinum combination chemotherapy and gastric adenocarcinoma cell lines (n=22) were used for qualification of gene expression profiling results by immunohistochemistry. A cisplatin-resistant gastric cancer cell line, AGS Cis5, and the oesophageal adenocarcinoma cell line, OE33, were used for in vitro validation investigations. Results: We identified 520 genes with differential expression (Mann–Whitney U, P<0.020) between radiological responding and nonresponding patients. Gene enrichment analysis (DAVID v6.7) was used on this list of 520 genes to identify pathways associated with response and identified the adipocytokine signalling pathway, with higher leptin mRNA associated with lack of radiological response (P=0.011). Similarly, in the independent cohort (n=154), higher leptin protein expression by immunohistochemistry in the tumour cells was associated with lack of histopathological response (P=0.007). Higher leptin protein expression by immunohistochemistry was also associated with improved survival in the absence of neoadjuvant chemotherapy, and patients with low leptin protein-expressing tumours had improved survival when treated by neoadjuvant chemotherapy (P for interaction=0.038). In the gastric adenocarcinoma cell lines, higher leptin protein expression was associated with resistance to cisplatin (P=0.008), but not to oxaliplatin (P=0.988) or 5fluorouracil (P=0.636). The leptin receptor antagonist SHLA increased the sensitivity of AGS Cis5 and OE33 cell lines to cisplatin. Conclusions: In gastro-oesophageal adenocarcinomas, tumour leptin expression is associated with chemoresistance but a better therapy-independent prognosis. Tumour leptin expression determined by immunohistochemistry has potential utility as a predictive marker of resistance to cytotoxic chemotherapy, and a prognostic marker independent of therapy in gastro-oesophageal adenocarcinoma. Leptin antagonists have been developed for clinical use and leptin and its associated pathways may also provide much needed novel therapeutic targets for gastro-oesophageal adenocarcinoma

Dopamine neurons modulate neural encoding and expression of depression-related behaviour

Major depression is characterized by diverse debilitating symptoms that include hopelessness and anhedonia1. Dopamine neurons involved in reward and motivation are among many neural populations that have been hypothesized to be relevant, and certain antidepressant treatments, including medications and brain stimulation therapies, can influence the complex dopamine system. Until now it has not been possible to test this hypothesis directly, even in animal models, as existing therapeutic interventions are unable to specifically target dopamine neurons. Here we investigated directly the causal contributions of defined dopamine neurons to multidimensional depression-like phenotypes induced by chronic mild stress, by integrating behavioural, pharmacological, optogenetic and electrophysiological methods in freely moving rodents. We found that bidirectional control (inhibition or excitation) of specified midbrain dopamine neurons immediately and bidirectionally modulates (induces or relieves) multiple independent depression symptoms caused by chronic stress. By probing the circuit implementation of these effects, we observed that optogenetic recruitment of these dopamine neurons potently alters the neural encoding of depression-related behaviours in the downstream nucleus accumbens of freely moving rodents, suggesting that processes affecting depression symptoms may involve alterations in the neural encoding of action in limbic circuitry

Input-specific control of reward and aversion in the ventral tegmental area

Ventral tegmental area (VTA) dopamine neurons have important roles in adaptive and pathological brain functions related to reward and motivation. However, it is unknown whether subpopulations of VTA dopamine neurons participate in distinct circuits that encode different motivational signatures, and whether inputs to the VTA differentially modulate such circuits. Here we show that, because of differences in synaptic connectivity, activation of inputs to the VTA from the laterodorsal tegmentum and the lateral habenula elicit reward and aversion in mice, respectively. Laterodorsal tegmentum neurons preferentially synapse on dopamine neurons projecting to the nucleus accumbens lateral shell, whereas lateral habenula neurons synapse primarily on dopamine neurons projecting to the medial prefrontal cortex as well as on GABAergic (γ-aminobutyric-acid-containing) neurons in the rostromedial tegmental nucleus. These results establish that distinct VTA circuits generate reward and aversion, and thereby provide a new framework for understanding the circuit basis of adaptive and pathological motivated behaviours.National Institutes of Health (U.S.) (Grant NIH NS069375)JPB FoundationNational Institute of Mental Health (U.S.

A dopaminergic switch for fear to safety transitions

Overcoming aversive emotional memories requires neural systems that detect when fear responses are no longer appropriate. The midbrain ventral tegmental area (VTA) dopamine system has been implicated in reward and more broadly in signalling when a better than expected outcome has occurred. This suggests that it may be important in guiding fear to safety transitions. We report that when an expected aversive outcome does not occur, activity in midbrain dopamine neurons is necessary to extinguish behavioral fear responses and engage molecular signalling events in extinction learning circuits. Furthermore, a specific dopamine projection to the nucleus accumbens medial shell is partially responsible for this effect. By contrast, a separate dopamine projection to the medial prefrontal cortex opposes extinction learning. This demonstrates a novel function for the canonical VTA-dopamine reward system and reveals opposing behavioural roles for different dopamine neuron projections in fear extinction learning

Modelling the impact of atherosclerosis on drug release and distribution from coronary stents

Although drug-eluting stents (DES) are now widely used for the treatment of coronary heart disease, there remains considerable scope for the development of enhanced designs which address some of the limitations of existing devices. The drug release profile is a key element governing the overall performance of DES. The use of in vitro, in vivo, ex vivo, in silico and mathematical models has enhanced understanding of the factors which govern drug uptake and distribution from DES. Such work has identified the physical phenomena determining the transport of drug from the stent and through tissue, and has highlighted the importance of stent coatings and drug physical properties to this process. However, there is limited information regarding the precise role that the atherosclerotic lesion has in determining the uptake and distribution of drug. In this review, we start by discussing the various models that have been used in this research area, highlighting the different types of information they can provide. We then go on to describe more recent methods that incorporate the impact of atherosclerotic lesions